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About
Across cancer types, immune checkpoint inhibitors have been shown to induce complete response, partial response, and stable disease after initial evidence of radiographic increase in tumor burden. Treatment beyond progression should be considered when the patient is stable (or improving) symptomatically and if tumor reassessment can be performed within a short period.
Full description
Preclinical evidence indicates that VEGF and VEGF-dependent angiogenesis may induce immune suppression in tumors by impairing antigen presenting cells and effector T-cells, and enhancing T-regulatory cells and monocytes. Thus, targeting VEGF may reprogram the tumor immune microenvironment to render cancers more vulnerable to immunotherapies. Indeed, the use of anti-VEGF strategies as an immunotherapy adjuvant has been associated with clinical benefit in multiple cancer types including HCC, and no new safety signals. While the clinical benefit of monotherapy axitinib in HCC is modest, use of axitinib as an immunotherapy adjuvant may circumvent primary resistance mechanisms to immune checkpoint inhibitors in HCC leading to more frequent or robust anti-tumor immunity.
Given the complimentary immune augmenting mechanisms of targeting VEGF and phosphatidylserine, combination axitinib, bavituximab, and avelumab, a PD-L1 antibody, represents a novel and rational immunotherapy regimen in HCC.
Enrollment
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Inclusion criteria
Patient must have a histologically confirmed diagnosis consistent with HCC; known fibrolamellar HCC, or combined HCC-cholangiocarcinoma will be excluded.
Locally advanced or metastatic disease
Availability of recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue block or slides (biopsied tumor lesion should not be a RECIST target lesion): 1) the biopsy or resection was performed within 2 years of AND 2) the patient has not received any intervening systemic anti-cancer treatment from the time the tissue was obtained.
Prior therapy is allowed provided the following are met: at least 4 weeks since prior locoregional therapy including surgical resection, chemoembolization, definitive radiotherapy with intent of disease control, or ablation. Provided target lesion has increased in size by 25% or more or the target lesion was not treated with locoregional therapy. Patients treated with palliative radiotherapy for symptoms will be eligible as long as the target lesion is not the treated lesion and radiotherapy will be completed at least 2 weeks prior to study drug administration.
Age ≥ 18 years
Child-Pugh Score A
ECOG Performance score of 0-1
Adequate organ and marrow function as defined below:
All men, as well as women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) 4 weeks prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
a. A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
Subjects are eligible to enroll if they have non-viral-HCC, or if they have HBV-HCC, or HCV-HCC defined as follows:
Ability to understand and the willingness to sign a written informed consent.
Patients who have received the vector, protein subunit, or nucleic acid COVID-19 vaccines are eligible to enroll.
Exclusion criteria
Prior liver transplant.
Prior systemic therapy directed at advanced or metastatic HCC.
Prior immunotherapy with IL-2, or anti-PD-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
Prior therapy with axitinib or any prior therapies with other VEGF pathway inhibitors.
Clinically significant, uncontrolled heart disease and/or recent events including any of the following:
Known human immunodeficiency virus (HIV) positive (testing not required).
History of cerebrovascular accident, transient ischemic attack, or thromboembolic events (including both pulmonary embolism and deep venous thrombus but not including tumor thrombus) within the last 6 months.
Hypersensitivity to IV contrast; not suitable for pre-medication.
Active or fungal infections requiring systemic treatment within 7 days prior to screening.
Known history of, or any evidence of, interstitial lung disease or active noninfectious pneumonitis.
Evidence of poorly controlled hypertension which is defined as systolic blood pressure >159 mmHg or diastolic pressure >99 mmHg despite optimal medical management.
Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication.
Active, known, or suspected autoimmune disease with the exception of subjects with vitiligo, type I diabetes mellitus, resolved childhood asthma or atopy. Subjects with suspected autoimmune thyroid disorders may be enrolled if they are currently euthyroid or with residual hypothyroidism requiring only hormone replacement. Subjects with psoriasis requiring systemic therapy must be excluded from enrollment.
Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the study or compromise compliance with the protocol (e.g. chronic pancreatitis, active untreated or uncontrolled fungal, bacterial, or viral infections, etc.).
Known history of active bacillus tuberculosis.
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg/day prednisone equivalent) or other immunosuppressive medications within 14 days of study administration. Inhaled or topical steroids and adrenal replacement doses >10 mg/day prednisone equivalents are permitted in the absence of autoimmune disease.
Patient who has received definitive radiotherapy with the sole intent of disease control ≤ 4 weeks prior to study entry. Palliative radiotherapy for symptomatic control (such as to bone metastases) is acceptable (if completed at least 2 weeks prior to study drug administration and no additional radiotherapy for the same lesion is planned).
Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects (tumor biopsy is not considered as major surgery).
Clinically apparent ascites on physical examination, ascites present on imaging studies is allowed.
Known severe hypersensitivity reactions to monoclonal antibodies (Grade 3).
Active gastrointestinal bleeding within previous 2 months.
History of any condition requiring anti-platelet therapy (aspirin >300 mg/day, clopidogrel >75 mg/day).
Diagnosis of any other malignancy within 5 years prior to screening visit, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix, or low-grade (Gleason 6 or below) prostate cancer on surveillance with no plans for treatment intervention (eg, surgery, radiation, or castration).
Prisoners or subjects who are involuntarily incarcerated.
History of leptomeningeal disease.
Symptomatic or clinically active brain metastases.
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after contraception and until the termination of gestation, confirmed by a positive hCG laboratory test.
Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV Ab(+) and detectable HCV RNA) at study entry.
Known prior or suspected hypersensitivity to study drugs or any component in their formulations.
Current use or anticipated need for drugs that are known strong CYP3A4/5 inducers, including their administration within 10 days prior to patient receiving the first study treatment, eg, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, St John's wort.
Patients with 2+ proteinuria on urine dipstick analysis and confirmed to have ≥2 grams of protein in a 24-hour urine collection.
Current use or anticipated need for treatment with drugs or foods that are known strong CYP3A4/5 inhibitors, including their administration within 10 days prior to patient receiving the first study treatment, (eg, grapefruit juice or grapefruit/grapefruit-related citrus fruits, ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir, troleandomycin, mibefradil, and conivaptan). The topical use of these medications (if applicable), such as 2% ketoconazole cream, is allowed.
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Data sourced from clinicaltrials.gov
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